best practices in ensuring quality standards when ... · comprehensive and timely information ......

Best Practices In Ensuring

Quality Standards

When Outsourcing To

Contract Manufacturers,

Licensees And Consultants

Alex D. Kanarek, PhD

BioProcess Technology Consultants, Inc.

Strategic Institute Quality & Regulatory Strategies Summit

Toronto, Ontario

March 5/6, 2009

From Clone to Commercial® 2

Agenda

Outsourcing Overview:

• Contract Manufacturers

• Licensing Out

• Use of Consultants

Regulatory Environment

CMOs, Contracts & Quality Agreements

Ensuring Quality by Partnering

PIP, Inspections & Audits

Key “Take-Home” Points

Discussion


CMO Outsourcing Overview

Transfer of Sponsor’s Technology

Product Development

Process Development

Manufacture: Clinical & Commercial

Process Validation (FDA: “Process Performance Qualification”)

Analytical Method Development & Validation


Best Practices in Technology Transfer

Have a well-defined TT process (written)

• Define roles and responsibilities clearly

Use software-based planning & scheduling devices such as “SuperPro” or MS Project to ensure no bottlenecks or conflicts

Some examples of pitfalls:

• Process uses custom raw materials (short supply?)

• Long lead equipment will delay project

• Instrument calibration tolerances do not match process needs

• Column packing requirements not clearly defined

• Mixing or filtration studies needed with different equipment

• Hold times may vary – stability concerns?


Example of “SuperPro” Equipment Conflict Chart


CMO Development Activities

Product Development, e.g.:

• Expression System Development/Improvement

• Cell Line Selection

• Formulation Development

Process Development, including:

• New Process Creation

• Existing Process Improvement

• Scale-up Studies

• Process Validation

CMO should have the expertise, but may not

FDA Rules on Validation are changing


Clinical and Commercial Manufacture

CMOs vary significantly in Capacity and Experience

Differing GMP Requirements for Phase I thro’ III

Commercial Manufacture uses Validated Processes and Methods

CMO must have Functional Quality Unit (QA/QC)


Analytical Method Development & Validation

Essential Part of Product Development

Often outsourced – possibly to another contractor

Contractor Provides Specialized Expertise & Equipment, for

• Characterization

• Potency Assays

• Impurities Profile

Problems

• Bringing method in-house

• Demonstrating robustness


Licensing Out

Early-stage Products

• Not usually done – originator loses control

• More often the research is sold to “Big Pharma”

• Or, there is a joint venture for further drug development

Products in Clinical Trial

• Licensee shares or undertakes the cost of clinical manufacture and testing and the trials

• If Licensee manufactures in-house, Quality Agreement needed

• If Licensee uses a CMO, the rules still apply

Approved Products

• Licensee must comply with all provisions of the Marketing Approval


Consultants

Work in-house or with other contractors

Provide specialized expertise and advice

Consulting agreement contains quality clauses

Typical Consultants’ Services:

• Product/Process Development

• Process/Method Validation

• In-house Audits for Regulatory Compliance

• Assistance with Training Programs

• Assistance with Documentation/Submissions

• Supplier Audits

• Selecting, Monitoring, Auditing CROs, CMOs; may be PIP


The Basic GMP Regulations (1)

Canada Federal Drug Regulations Division 2, Part C

• Need for Establishment License

• GMP Guidance 2002, revised 2007 - draft for comments

Defines Quality Management System, QA/QC

• QA ensures that “Outsourced activities are subject to appropriate controls and meet GMP requirements”

• Specifies qualifications/experience of responsible staff

USA Regulations, 21CFR 210 + 211 for all drugs, 600 series for biologics, 820 for devices

• All facilities must be registered

• No specific mention of outsourcing in 21CFR211

• Guidance on “split” manufacture of biologics Nov. 2008


However, A Recent FDA Warning Letter Stated:

“Specifically, your firm has not established and approved quality system procedures that delineate the specific responsibilities and manufacturing operations for each of your contract manufacturing facilities…”


The Basic GMP Regulations (2)

EU Regulations EUDRA Volume 4 + Annexes

• Chapter 7 “Contract Manufacture & Analysis “

Defines responsibilities of both parties clearly.

Some following slides are based on this chapter.

ICH Q7: Guidance on GMP for APIs

• Section 16: Specific provisions for contract manufacturers

Must comply with GMP – sponsor to evaluate

Must allow sponsor audits

Written contract

Sponsor approves changes


General GMP Provisions

USE QUALITY SYSTEM MANAGEMENT (& Risk Evaluation) for:

Proper Design & Operation of Facilities & Equipment

Control of Raw Materials and Components

Adequate Qualification & Training of Staff

Written Procedures for all Critical Activities

Quality Control of In-Process & Final Product

• To preset specifications

Full Records of Manufacture & Testing

Validation of Processes and Test Methods

Process Change Control & Documentation


The Ideal CMO:

Has the competence to manufacture/test the product

Complies with the quality standards of the sponsoring company

Has the necessary legal manufacturing authorizations

Has an infrastructure and culture capable of providing accurate, comprehensive and timely information

Provides a good fit with the Sponsor’s corporate culture

Has the capacity to meet product demand for clinicals or sales

Can supply the product at an acceptable cost/dose

Has commitment to your business and can deliver orders on time and in full

Is a secure business capable of long-term tenure of supply, which invests sufficiently in maintaining up-to-date technologies.


Managing the Relationship

The Sponsor should:

• Provide dedicated project management/contact person(s)

• Maybe a Person in the Plant (PIP)

• Maintain clear communication channels

• Provide for conflict resolution

• Manage overly optimistic deliverable requirements

The CMO should:

• Be attuned to a cultural fit with the sponsor

• Be a good partner

• Be responsive to sponsor’s needs & concerns

• Manage overly optimistic forecasts


CMO Contracts & Quality Agreements

There must be a Written Contract

Defining the Responsibilities of:

• The Sponsor

Technology Transfer

QA/Regulatory Support

• The Contractor

To use established processes or develop new ones

To comply with GMP

Providing an Assurance of Quality

• In Contract or Separate Agreement

All arrangements must be in accordance with the marketing authorization (if it exists)


Define the Responsibilities (1)

“The Contract Giver is responsible for assessing the competence of the Contract Acceptor to carry out successfully the work required and…

For ensuring by means of the contract that the principles and guidelines of GMP ... are followed.” - EUDRA Vol. 4, Chapter 7.


In Other Words...

The Sponsor

• Retains overall responsibility for compliance

• Must have a Quality Assurance/Quality Control unit

• Must assess, monitor and audit the CMO’s operations

• Must perform annual product quality review with CMO

Will prepare and submit the CTA, NDS, etc. (IND, NDA)



“The Contract Acceptor must have adequate premises and equipment, knowledge and experience, and competent personnel to carry out satisfactorily the work ordered by the Contract Giver.

Contract manufacture may be undertaken only by a manufacturer who is the holder of a manufacturing authorization.” EUDRA.


In Other Words…

The CMO

• Must be in compliance with GMP, according to the phase of manufacture

• Must have a QA/QC Unit

• Must work to Master Formulae (MBR) and maintain full Batch Production Records

• Must monitor and audit internally

• Must be licensed or registered with Regulatory Agency



Consultants and Contract Auditors

• Are required to have appropriate training and qualifications

• Must comply with GMP

• Contract Giver must record

Consultant’s qualifications

The services provided


The Quality Agreement

“Quality systems call for contracts (quality agreements) that clearly describe the materials or service, quality specification responsibilities, and communication mechanisms” – FDA

Should Summarize:

• The Sponsor’s expectations

• The CMO’s commitment

Should Contain:

• A Reference to the relevant Regulations

• The Agreed Specifications of In-process and Final Product

• Provision for QA Oversight (by Sponsor and Contractor)

• System for product approval/release

Should Define the handling of Deviations/Errors/OOS Results


Quality Agreements – Opinion from FDA

“Should clearly outline all responsibilities of both

parties for notification of manufacturing-related

issues to one another…”

“Should contain a full description of all reporting

relationships for issues related to contract

manufacturing operations based upon the nature

of the relationship”

Dr. Mark Elengold, CBER Deputy Director, Operations


Questions to Answer – Opinion from FDA

How is information shared specific to investigations of deviations?

How is the contract manufacturer going to evaluate changes in equipment and facility use that may impact on the

product, and how will they notify the license holder? Who has ultimate responsibility for the product and does this

entity have full access to all potential product impacts or contractor operations?

Elengold


Compliance Assurance - Initial Audit

Investigate:

• The competence of the Contractor’s staff,

• His history of successful projects,

• His SOPs for all manufacturing & control operations,

• The results of previous Audits and Regulatory Inspections, DMFs filed

Inspect the plant, QMS, operations, validation reports, production records etc.


Compliance Assurance – During Operations

Clearly define all critical GMP compliance requirements in the contract

Have a Person in the Plant (PIP) if necessary

Arrange for periodic QA visits to inspect (audit) actual manufacturing of the contracted product

Obtain process validation reports as they are generated

Ensure QC testing is done with qualified methods

Ensure that production/testing records are complete and accurate.

Ensure notification of all process/testing deviations and that all OOS results are investigated


Ongoing Surveillance – FDA’s Recommendations

Ask to be notified of all changes which could affect the processing of your (approved) product

• New equipment

• Change in key personnel

• Change in test methods

• Change in SOPs

Ask to be notified when the contract facility is visited by the FDA

• Ask for a copy of all FDA-483s which are issued to the firm

Ask to be notified if a test result was obtained as a result of a re-test (and why…)


The Person in Plant – Friend…?

The primary conduit of information between the two companies

Will help coordinate production schedules, document reviews/approvals, and general project-related tasks

Will personally observe batch manufacturing activities

May conduct site audits, if qualified

Must be able to communicate progress, issues, concerns and questions to sponsor colleagues

And communicate responses to CMO staff

CMO will expect the PIP to have authority to participate in on-the-spot trouble-shooting and be able to make decisions regarding product quality when anomalies occur, But…


The Person in Plant – …or Foe?

It is rare for the PIP to have the authority to approve products for continued processing when a process deviation or OOS is encountered – Sponsor’s QA Unit must be involved

Must be a consummate politician…

• Will always be the outsider looking in

• Everyone at the CMO is aware that they are being observed

• May be a drain on CMO resources

May have to function as a partner, mentor, auditor and project sponsor simultaneously

Must always be careful not to interfere with operations

• Can create liability problems

Can enhance or destroy a sponsor’s relationship with a CMO


Sponsor’s Inspections & Audits

Use the Six Systems Approach:

“Compliance Program Guidance Manual

for FDA Staff: Drug Manufacturing Inspections Program”,

Implemented February 2002

Apply Risk Analysis to determine critical processes/procedures to inspect


The Six Systems

1) Quality System - Always inspect this! a) SOPs & other Document Management

b) QA Audit Reports, Internal & External

c) Regulatory Inspection Reports (Canada Inspection Exit Notice, FDA Form 483), Warning Letters

2) Facility & Equipment – walk through a) Environmental Control & Monitoring

b) Staff & Materials Movement Control

c) Equipment Placement, Maintenance & Calibration

d) Cleaning Validation

3) Materials a) Raw Material & Container Specifications

Vendor Audits


The Six Systems, continued

4) Production

a) SOPs for standard operations – being followed?

b) Critical procedures qualified/validated?

c) Batch records – critical measurements countersigned?

5) Packaging & Labeling – as needed

6) Laboratory Control

a) Using agreed test procedures & specifications?

b) Qualified/validated methods

c) OOS Investigations


Data Audits

Should confirm the accuracy and integrity of reported data and results.

Involve comparison of batch records and reports with “raw data”, e.g.:

• Operators’ in-process records,

• Analysts’ laboratory notebooks.

Should also cover deviation reports and failure analyses.


What Can Go Wrong?

A 2007 survey revealed the following TOP 6 Categories of COMPLAINTS:

Type of Complaint Percentage of Respondents

Competence 21.4%

Quality 13.1%

Communication 13.1%

Delivery 11.9%

Customer Service 10.7%

Costs 7.1%

Source: Contract Pharma


Some Recommended Best Practices

Appoint a “Technical Product Owner”

• To follow product over the entire life cycle

• Continuity is critical

External Quality Manager must be technically competent

• Often a Sponsor’s resource constraint

Key Performance Indices should be well defined

Establish clear time-frames for responses either way

Encourage the CMO to Think, not just Do

• Continuous Improvement is the Aim

Remember - Your CMO is Your Partner


Finally…

Questions?

Comments?

Thank You

[email protected]

519-856-4710

BioProcess Technology Consultants, Inc.

289 Great Road, Suite 303 Acton, MA 01720 USA

1-978-266-9101 (phone) 1-978-266-9152 (fax)

[email protected] www,bioprocessconsultants.com

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